Percutaneous transluminal coronary angioplasty (“PTCA” or “angioplasty”) procedures have been performed for many years as an adjunct to correcting vascular disease in patients. Angioplasty procedures involve the insertion, through the vascular system, of a catheter having a balloon that is placed across a lesion or blockage in a coronary artery. The balloon is then inflated to compress the lesion or blockage against the arterial walls, thereby opening the artery for increased blood flow.
In some cases, however, the goal of the angioplasty procedure is defeated at least in part by a complete or partial reclosure of the artery at or near the compressed lesion or blockage. Two mechanisms are believed to be principally responsible for reclosure of the artery. The first mechanism is recoil, which is a mechanical process involving the elastic rebound of the compressed lesion or blockage. The second mechanism is restenosis, which is believed to be caused by proliferation of the smooth muscle cells present in the artery walls near the lesion or blockage. Restenosis can occur over a period of several weeks or months after the PTCA procedure.
Many different methods have been employed to limit the effect of restenosis, including radiation treatments and various drug therapies, delivered locally and systemically, to slow proliferation of the smooth muscle cells. Recoil of the arterial walls can be prevented by using stents, which can be temporarily or permanently deployed within the artery to mechanically maintain patency of the artery. Stents are very effective at carrying out this task, but they may also irritate the contacting arterial walls, which may in turn encourage additional restenosis.
Gene therapy has been used for diverse medical purposes, including slowing proliferation of smooth muscle cells. Genes are usually delivered into a patient's cells through a vector, such as a retroviral vector, whose DNA is genetically engineered to include a desired DNA sequence. Alternatively, nonviral gene transfer methods can be used, such as plasmid DNA vectors, along with polymeric carriers, DNA condensing agents, lipofection and receptor mediated delivery vectors.
In connection with angioplasty, incorporation of appropriate DNA molecules into the coronary artery walls near the treatment site can be beneficial to inhibit restenosis. A polymer-coated stent can be used as the delivery vehicle for the DNA, in addition to maintaining patency of the artery following PTCA.
However, effective delivery of high-molecular-weight therapeutic agents, such as DNA and any associated vector, can entail large amounts of therapeutic agent and long delivery times. Large amounts of polymeric material provided as a coating on the stent may, therefore, be required to adequately incorporate the therapeutic agent and ensure controlled and extended release of the therapeutic agent over a required period of time. Consequently, the polymeric coating may become relatively thick, increasing the susceptibility, during expansion of the stent, to cracking of the coating. Such cracking can reduce the effectiveness of the coating to deliver the therapeutic agent therefrom, among other consequences. Moreover, because some medical devices such as stents have limited surface areas for disposition of a polymer coating, it would be desirable to provide a coating that actually enhances the uptake of the therapeutic agent by the tissue of interest.
The manufacture of medical devices with high-molecular-weight therapeutic agents in polymer matrices can also present processing difficulties. For example, relatively high shear stresses are commonly encountered while processing a mixture of a polymeric material and a therapeutic agent. In the case of certain high-molecular-weight therapeutic agents such as polynucleotides (e.g., plasmids), for example, these shear stresses can, in turn, disrupt the conformational and/or structural integrity of the therapeutic agent.
Moreover, certain biostable polymers that are highly biocompatible (e.g., polystyrene-polyisobutylene copolymers) may in some cases provide insufficient mass transport therethrough of high-molecular-weight therapeutic agents after deployment, limiting their utility in medical devices that deliver such agents.
Accordingly, there is a need for coatings for stents and other medical devices that release high-molecular-weight therapeutic agents in a controlled fashion over a period of time and do not suffer from the foregoing and other disadvantages. The coatings should, therefore, contain a therapeutically effective amount of high-molecular-weight therapeutic agent and provide adequate control of the release of that therapeutic agent. In addition, in the case of expandable medical devices such as stents and balloons, the coatings should resist cracking that may occur during expansion of the medical device. Moreover, the conformational and structural integrity of high-molecular-weight therapeutic agents such as DNA should be preserved to the greatest extent possible during manufacture of the medical device.